This application for a Mentored Patient-Oriented Clinical Scientist Development Award (K23) seeks support for Katherine Bergwerk, MD, a staff ophthalmologist at Cedars-Sinai Medical Center (CSMC), who recently completed a Clinical fellowship in Ophthalmic Genetics at CSMC and U.C.L.A.'s Jules Stein Eye institute. Under the mentorship of Julie R. Korenberg, MD, PhD, and Yaron S. Rabinowitz, MD, Dr. Bergwerk will pursue investigation of gene loci for keratoconus and other ocular abnormalities in patients with partial trisomies and tetrasomies of chromosome 21. Identifying a gene for keratoconus may allow for early detection of the disease and may enable medical therapy to be developed to retard its progression. This will obviate the need for the current therapy of multiple complex contact lens fittings or corneal transplantation surgery. Keratoconus is a major cause of visual disability and one of the leading causes for penetrating keratoplasty in the United States. In the process of completing comprehensive ocular examinations on these rare patients for keratoconus, attempts will be made to make genotype-phenotype correlations of other eye abnormalities in patients with Down syndrome. Dr. Rabinowitz is a prominent researcher in the field of ophthalmic genetics, who has established a candidate region for a keratoconus gene locus. This region is a 5.4 centimorgan (cM) region which is 11 cM distal to the centromere on the long arm of chromosome 21 (see appendix A). Review of the literature suggests that keratoconus may occur as much as 300 Xs more commonly in Down syndrome patients than in the general population. Dr. Korenberg is a renowned molecular geneticist who has served on the Human Genome Project for defining genes on Chromosome 21. Her unique population of partial trisomy Down syndrome patients are the ideal group to use in refining a gene locus for keratoconus and to make genotype- phenotype correlations of ocular features of Down syndrome. Under Dr. Rabinowitz and Dr. Korenberg's mentorship and with institutional support from the Divisions of Medical Genetics and Ophthalmology at CSMC, Dr. Bergwerk will further her training in clinical genetic research, and enhance her skills in clinical and molecular genetics. Dr. Bergwerk aspires to achieve her goal of becoming an independent investigator who is capable of solving clinical problems in a research laboratory.